OBITUARY Carl-Ivar Brändén 1934–2004

Shuguang Zhang, Alexander Rich, Joel L Sussman & Alan R Fersht

Carl-Ivar Brändén of the Karolinska Institute died on April 28, 2004, higher language so the whole program was written in machine code. two weeks short of his 70th birthday. Carl (“Calle” to his friends and It took six months for Brändén to write a detailed flow chart, four family) was born in a tiny village in Lappland in the far north of months for Åsbrink to write the machine code and one year for them . His father was the local schoolteacher and Carl spent his first to debug the program. Over the next ten years this program was used six years at school under his own father’s supervision. There were only by the entire Scandinavian crystallographic community and was top- 15 children in the school, all in the same classroom, so when one age rated in the use of computer time for both BESK and its much group was in session, the other pupils were studying on their own. He improved successor FACIT. learned at an early age to concentrate on his work and ignore the noise In order to graduate, Carl had to take another course. His choice was around him. The village was poor and scholarly pursuit was unheard biochemistry. This decision completely changed his plans for the of. The climate consisted of nine months of winter and three months future, because he realized that he could apply his knowledge of crys- of cold wind; but was wonderful with beautiful lakes filled with tallography to scientifically important and intellectually stimulating lots of fish and deep forests full of berries and mushrooms and trees to problems in biology. He wanted immediately to move into the field of climb. Carl had the marvelous experience of being surrounded by a protein . The obvious place to learn was the MRC http://www.nature.com/natstructmolbiol herd of 10,000 reindeer. Laboratory for Molecular Biology (LMB) in Cambridge, UK. As Carl left home at the age of 13 with the intent of becoming a school Brändén himself put it, one year as a postdoctoral fellow in the labora- teacher. He won a scholarship to study mathematics and chemistry at tory of Sir John Kendrew at LMB converted Carl from a rather igno- . While studying in the chemistry laboratory, he was rant chemist to a devoted molecular biologist and he studied the invited by the acting chairman of the inorganic chemistry department, structure and function of proteins from that point on. Ingvar Lindqvist, to do a Ph.D. in his group. At the time, it was unusual LMB was in those days one of the most exciting and stimulating for a major in mathematics to work in chemistry, but since Lindqvist’s places for a young postdoctoral fellow. had built up the research focused on X-ray crystallography of small inorganic com- laboratory with an incredible ability to choose the right people and let plexes, he was eager to obtain students with a mathematical back- them work independently. Perutz himself was working on the high- ground. Carl was extremely flattered and accepted without hesitation. resolution structure of . Jacques Monod visited to lecture As Carl aptly put it, he never had a single boring day thereafter. and discuss with Perutz his latest development on the theory of In 1960, Carl attended a summer school in Manchester on modern allosteric transitions, for which the conformational changes in hemo- methods of X-ray crystallography organized by D.W.J. Cruickshank. At globin played an important role. Francis Crick and Sydney Brenner

© 2004 Nature Publishing Group the time, determining the structure of even a simple small molecule were working on the genetic code and attracted an endless stream of required intense computing power. Structure factors were calculated stimulating visitors. Fred Sanger’s group was sequencing several large using mechanical calculators to add precomputed sine and cosine func- proteins and interacted frequently with the structural biologists. tions listed on so-called Beevers-Lipson strips. Most people then used a Aaron Klug had just moved in from London and was developing his homemade analog computer for Fourier summations, the Hägg- methods of optical filtering and three-dimensional reconstruction Laurent machine, where three-dimensional Fourier sums were broken from electron micrographs. The daily interactions with the postdocs down into three successive one-dimensional summations. In a series of in structural biology provided Carl with a network of lectures Cruickshank described how the method of least squares could colleagues who later became lifelong friends—Michael Rossmann, be applied to the refinement of X-ray structures and also outlined his David Blow, Lubert Stryer, Richard Dickerson, Allen Edmundson, Ken program for one of the first digital computers in the United Kingdom. Holmes, and Herman Watson, among others. Inspired by these lectures, Carl developed a collaboration with Stig At the LMB, Carl rapidly engaged himself in writing a computer Åsbrink of Stockholm University to write a similar program for the program for the refinement of myoglobin by the least squares first Swedish electronic computer, BESK. This computer had a mem- method. The structure had been solved a few years earlier and higher- ory of 1,000 words, equipped with a larger magnetic drum memory, resolution data had been collected by David Phillips at the Royal and used paper tape for input and output. There was no compiler for a Institution in London using a newly developed linear diffractometer. John Kendrew and Herman Watson were using these data in combi- S.Z. is at the Center for Biomedical Engineering and the Center for Bits nation with approximate coordinates of the myoglobin structure for and Atoms, Massachusetts Institute of Technology, Cambridge, refinement by Fourier synthesis, but better methods were needed. Massachusetts 02139-4307, USA (e-mail: [email protected]), A.R. is at Brändén and Holmes together designed a program using exact con- the Department of Biology, Massachusetts Institute of Technology, straints and a 6 × 6 block diagonal matrix. It turned out to be a non- Cambridge, Massachusetts 02139-4307, USA, J.L.S. is at the Department trivial problem to adopt this method to available computers. Even of Structural Biology, Weizmann Institute of Science, Rehovot 76100, though they were using the fastest available machines in the United Israel (e-mail: [email protected]), and A.R.F. is at Cambridge Kingdom, IBM 709 and later 7090, they had to invent several tricks to University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, reduce computing time and storage space. The final version of the UK (e-mail: [email protected]). program required 12 magnetic tape stations for intermediate storage.

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When the program was finished they estimated that each cycle of provided Carl with the wonderful opportunity to explore ADH struc- refinement would require 16 hours of computing time on the 7090 at ture and function from many perspectives. the IBM computing center at a considerable cost. This type of con- Carl always liked to face grand challenges. In the late 1970s he took strained refinement was well ahead of its time, but methods very sim- on an ambitious project to solve the crystal structure of Rubisco, an ilar to what Brändén and Holmes developed in the early 1960s were that catalyzes the initial carbon dioxide fixation in bacteria rediscovered by others in the late 1970s and are now used routinely and plants, after reading a report from the US National Academy of for macromolecular crystallographic refinement. Sciences. He first recruited Inger Andersson, a biochemist from In 1962, during Carl’s time at LMB, Crick, Watson and Wilkins won Michael Zeppezauer’s group in Saarbrucken, and later a graduate stu- the Nobel Prize in medicine and Perutz and Kendrew won the Nobel dent, Ylva Lindqvist, whose father was Carl’s Ph.D. thesis mentor. He Prize in chemistry. A celebration party was arranged at Crick’s home, also recruited Gunter Schneider from Hans Eklund’s lab as a postdoc- The Golden Helix, quite memorable for the fireworks arranged by toral fellow. He collaborated with George Lorimer then at DuPont Mark Bretscher. During the party, Perutz made a speech. He said that (Wilmington, Delaware, USA), an expert on the biochemistry of the reason why he and Kendrew had succeeded where others had failed Rubisco, and obtained grams of purified Rubisco protein. Within a few was that they had been so ignorant about crystallography that they did months he had obtained crystals and in 1986 they published the X-ray not know that it was impossible to solve a protein structure. As Carl structure of this bacterial enzyme. This structure became a turning remarked later, “knowledge is fine but too much is inhibitory for point in the studies of Rubisco. Not only did it provide the first breakthrough science.” detailed picture of the active site of Rubisco, but it also provided the After returning to Uppsala in 1963, Carl formed a long-time collab- fold of the large subunit of all Rubisco molecules, which subsequently oration with Hugo Theorell and Åke Åkesson of the Karolinska aided structural and functional interpretation of all Rubisco . Institute, who were biochemistry experts on alcohol In collaboration with Stefan Knight, Staffan Normark and Scott (ADH). With an equipment grant Hultgren, Carl determined the from the US National Institutes of crystal structure of a bacterial Health, Brändén took up the struc- chaperone protein, PapD, http://www.nature.com/natstructmolbiol tural determination of this enzyme. when the study of molecular Awaiting lab facilities, Eila Cedergren- chaperones was an emerging Zeppezauer, Carl’s first graduate stu- field. dent, obtained the ADH crystals in her In the mid 1980s, when kitchen refrigerator. After ten years of protein engineering started to active pursuit, the structure was become a common tool in solved. Brändén and his colleagues biochemistry and molecular eventually postulated a detailed biology, Carl realized that mechanism of action based on protein structures would not structure determinations of a number only become increasingly of complexes in two different confor- important, but also would be mations. transformed from a pure aca- In 1966, Carl attended the first demic pursuit to an impor-

© 2004 Nature Publishing Group international symposium on methods tant tool of molecular life of protein crystal structure determina- sciences and beyond. Without tion at the Hirschegg ski resort in the Austrian Alps. The meeting was a deep understanding of the principles of protein structure, protein organized by Max Perutz and Walter Hoppe from Munich and had engineering would be reduced to tinkering. In the midst of a lot of attracted 16 participants who comprised almost the entire protein activities, he approached John Tooze of the European Molecular crystallography community. It was an ideal size for intensive discus- Biology Organization to be co-author of a textbook on protein struc- sions on developing novel methods, both experimental and theoreti- tures. This beautiful book, Introduction to Protein Structure, with ele- cal. In 1969, at a meeting in Konstanz, Germany, Michael Rossmann gant hand-drawn (rather than computer-generated) illustrations compared his structure of LDH with Brändén’s ADH. To their delight and astonishing clarity has had a tremendous impact on molecular they could identify similar features in parts of the subunits. Although biologists, and especially on graduate students and those who wish no one believed their structures at the time, they had in fact discov- to know more about structural biology but do not have any back- ered a new protein fold. They showed that even when there is no sig- ground in the field. Robert Gallo, the co-discoverer of the HIV virus, nificant sequence identity, there could be a similar structural fold, was so fond of this book that he once remarked at a meeting that he which Michael Rossmann called a “molecular fossil”, that is common kept this book at his bedside and read it with great pleasure. One of in a class of functionally similar enzymes. us (S.Z.), while working with Alexander Rich, was attracted to the In collaboration with Martin Karplus, Carl’s group studied the elegant book early on, and later used it for teaching a course on mol- dynamics of ADH domain rotation using computer simulations and ecular structure of biological materials at the Massachusetts Institute found no significant energy barrier in rotating the domains from one of Technology (MIT). This book has stimulated numerous engineer- form to the other. Meanwhile one of Hugo Theorell’s students, Hans ing students who had no biological background to move into biology Jörnvall, determined the amino acid sequences of several different to design new materials using the protein motifs illustrated in the alcohol . Carl also had frequent long-term visitors book. After all, these simple molecular motifs are the diverse and from outside Sweden who were engaged in chemical or biochemical remarkable structures in proteins that determine their function. work on ADH in their home laboratories. The longest-lasting and per- Carl maintained a keen interest in developing new methods for sonally most rewarding visitor was the biochemist Bryce Plapp from structural biology, a crucial part of modern biology. He realized that the University of Iowa. These extensive collaborations and friendships new technology and tools can accelerate science as a whole. He spent

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five years as research director at the European Synchrotron Radiation lar biology and often traveled throughout Europe and to Israel to Facility in Grenoble, France. He was responsible for establishing interview prospective fellows. At the same time he was chairman of the facilities for chemistry, biology and medicine, and managed to pro- Chemistry Committee of the Swedish Natural Science Research mote strong facilities for structural biology. He realized that this was Council and a member of the board of the council as well as a board a golden opportunity for extending the frontiers of structural biol- member of the Swedish Foundation for Strategic Research. He was a ogy by determining the structures of very large molecular complexes board member of a large consortium for functional genomics not only as well as collecting data from very small crystals (now down to in Sweden but also in the United States, as well as a member of science ∼10 µm3). In addition, it was possible to study the dynamics of bio- advisory committees and evaluation committees of several institutes chemical reactions by time-resolved crystallography in the microsec- and synchrotron sources worldwide. Carl and Wayne Hendrickson ond range, obtain fiber diffraction patterns of single protein fibrils launched the journal Structure in 1993. and explore novel medical applications. In the late 1990s he partici- In November 2002, Carl was diagnosed with lung cancer and he pated in designing the ultimate tool for structural biology, a free immediately resigned his activities. In typical fashion, he wrote: electron laser with femtosecond-pulse diffraction combined with “I have decided that since I have devoted almost my entire life to sci- three-dimensional holographic instant data collection. He was very ence I also want to contribute to science towards the end of my life by excited to learn that a group at MIT is developing a scalable participating in clinical trials based on novel compounds such as pro- microslot probe for electromagnetic microstructure instrumenta- tein kinase inhibitors. I feel confident that ten years from now lung tion that could complement the free electron femtosecond-pulse cancer will be regarded as a curable disease thanks to the steady laser-holography system. advancement of our knowledge of the molecular biology of cancer.” Carl was also keenly aware of the importance of multidisciplinary He also wrote: “From a human point of view it has been a fascinating collaboration. He often collaborated with people from very different experience to suddenly realize that the end of my life is in sight. fields and promoted such collaboration on an international scale. Carl Looking back, I find great comfort in the fact that I have had a full and was always very warm and kind to young scientists regardless of age and rich life with many friends all around the world, been blessed with background and fostered young talent, such as Alwyn Jones. children and grand children and never had a boring moment thanks to http://www.nature.com/natstructmolbiol Carl’s wife, Dr. Malin Åkerblom, works in an organization within my scientific activities.” He was to receive a honorary doctoral degree Uppsala University that supports basic science projects in the poorest from the Karolinska Institute on May 14, also his 70th birthday, to countries of the third world, such as Tanzania, Zimbabwe, Sri Lanka honor him for his lifetime achievement. and Bangladesh. Through her work Carl had the opportunity to Eva Klein, a renowned immunologist at the Karolinska Institute develop a deep insight into the problems that face science in these who also discovered natural killer cells, once remarked, “I have always countries. He also had the privilege of getting to know a number of tried to find a great scientist, who is genuine, gentle, modest, honest bright and devoted scientists from developing countries who struggle and accessible. I have found the person, Carl Brändén.” His passion for against difficult odds. He remarked: “From a global perspective of sci- science, wisdom, friendship and scholarship will be missed by a much ence policy it is a dreadful waste of human resources that the industri- wider community for years to come. alized world supports mediocre scientists in large numbers while many bright young people in the Third World are deprived of the pos- Note: Much of this obituary is based on Carl Brändén’s autobiography, sibility to make their impact on the development of science.” which he called, “My Own Obituary, My Life in Science: from Reindeers Carl also spent considerable time on science policy and in the capac- to Synchrotrons.” The autobiography will be published in Comprehensive

© 2004 Nature Publishing Group ity of journal editor. He was one of five members of the Nobel Biochemistry 43: A History of Biochemistry-Selected Topics in the Committee for the Chemistry Prize. He was chairman for three years History of Biochemistry. Personal Recollections VIII (ed. Semenza, G., of the EMBO fund committee for postdoctoral fellowships in molecu- Elsevier, Amsterdam, 2004). ISBN: 0444517227.

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